The invention relates to a preparation composed of a fixed oil of vegetarian [sic] or animal origin, calcium hydroxide, a dihydric or polyhydric alcohol and, where appropriate, pharmaceutically acceptable excipients, to the preparation of a mixture of this type, to the use of a mixture of this type for collagen regeneration, and to the use of a mixture of this type for producing a medicine for promoting collagen regeneration in vivo.
Bone consists of about 60% mineral substance (hydroxyapatite, calcium phosphate) and about 40% organic material, principally collagen. Bone metabolism is determined mainly by the interplay of bone-constructing cells (osteoblasts) and bone-degrading cells (osteoclasts and osteocytes), whose activities in healthy bone are in a balanced relationship.
Bone formation can be divided into two main phases, (a) the synthesis of organic tissue (collagen synthesis) and (b) the deposition, which follows this and is mediated by so-called matrix vesicles, of mineral substance in the previously provided organic matrix.
The connective tissue protein collagen accounts for most of the organic substance in bone. The protein consists of three helically coiled polypeptide chains whose amino acid composition may vary, which leads to a diversity of individual types of collagen. It is common to all types of collagen that the collagen fibers have exceptionally great mechanical strength. This strength is based on a multiplicity of intra- and intermolecular linkages of the collagen fibers which, in this way, form the dense collagen fiber network of connective tissue. Bone tissue isxe2x80x94as already mentionedxe2x80x94formed by deposition of mineral substances (hydroxyapatite and calcium phosphate) in this network. Bone construction as a result of growth or regeneration processes is always preceded by collagen biosynthesis.
To date, in cases of bone injury of any cause, the bone regeneration process has been left to itself, at the most assisted by antibiotics and corticoids in order to prevent any risk of infection compromising the healing process.
Several factors able to influence bone formation and regeneration have also been described. These are mainly physical factors (mechanical and electrical forces), hormones (for example parathyroid hormone, calcitonin, insulin, glucocorticoids, 1,25-OHD3[sic]) and a not firmly defined group of growth factors with protein characteristics (osteochinin [sic], osteonectin, xe2x80x9cinsulin-like growth factorsxe2x80x9d)xe2x80x94cf. S. Wallach, L. V. Avioli, J. H. Carstens jun. xe2x80x9cFactors in Bone Formationxe2x80x9d, Calcified Tissue International 45: 4-6 (1989)). The effect of the hydrogen ion concentration (pH) on the metabolic processes in bone regeneration has not as yet been adequately investigated.
Dietz describes in DE-A-42 40 713 the use of a mixture of calcium hydroxide and neatsfoot oil for collagen regeneration following bone injuries. This preparation of calcium hydroxide and neatsfoot oil suffers, however, from the fact that its stability is very limited as a consequence of saponification. This may impair the effect of the mixture.
The invention was accordingly based on the object of indicating an improved mixture with long stability for the specific external influencing of the bone regeneration process through stimulation or initiation of collagen regeneration.
It has now surprisingly emerged that it is possible by using a preparation composed of calcium hydroxide, a dihydric or polyhydric alcohol and a fixed oil of vegetarian [sic] or animal origin and, where appropriate, pharmaceutically acceptable excipients to improve the stability of the preparation markedly and thus, on use of this preparation, in or for bone injuries, the extent of collagen regeneration in vivo is improved.
The present invention thus relates to preparations which comprise calcium hydroxide, a dihydric or polyhydric alcohol and a fixed oil of vegetarian [sic] or animal origin and, where appropriate, pharmaceutically acceptable excipients.
The present invention further relates to a process for producing a preparation of this type by means of mixing the calcium hydroxide and the dihydric or polyhydric alcohol and, where appropriate, pharmaceutically acceptable excipients into a fixed oil of vegetarian [sic] or animal origin.
The present invention further relates to the use of a preparation of this type for collagen regeneration.
The present invention further relates to the use of a preparation of this type for producing a medicine for promoting collagen regeneration in vivo.
Barium sulfate-containing mixtures of calcium hydroxide and neatsfoot oil have been used in dentistry as root-filling paste (DE-C 29 32 738). Mixtures of carboxylate cement, calcium hydroxide and neatsfoot oil have likewise been used in dentistry as temporary fixing means for provisional copings (DE-C 34 13 864). The task of the calcium hydroxide in the former case is to convert the acidic environment in the root canals into an alkaline one, resulting in the elimination of inflammations and gradual formation of a hard tissue barrier. In the latter case, the pulpitis-prophylactic effect of calcium hydroxide is utilized. The neatsfoot oil serves in both cases as a pasting auxiliary in order firstly to ensure simple and complete filling of the root canals with the actual active ingredient calcium hydroxide (and the contrast agent barium sulfate), and secondly to slow down the setting of the temporary fixing means for provisional copings so that the calcium hydroxide is also able to penetrate through the fine dentinal tubules to the pulp and display its effect there. Neither of the two references gives the slightest hint that the mixture according to the invention is able to induce extensive collagen regeneration as prerequisite for bone regeneration.
The term, which is novel according to the invention and is used hereinafter, xe2x80x9cpreparationxe2x80x9d refers to a pharmaceutical preparation (sometimes also referred to as mixture hereinafter) which contains at least the abovementioned ingredients. It is particularly suitable for administration to humans or animals for research into collagen regeneration as prerequisite for bone regeneration.
The ingredients of the mixture according to the invention are described in more detail below:
The fixed oils of vegetarian [sic] origin which can be used may comprise one or more ingredients of the following vegetarian [sic] oils:
Soybean, sunflower, rape seed, cottonseed, linseed, castor, palm, palm kernel, coconut and olive oils.
The fixed vegetarian [sic] oils which can be used are preferably fixed vegetarian [sic] oils with high stability on heating, such as soybean, sunflower and olive oils, in particular olive oil.
The fixed animal oils which can be used may comprise one or more ingredients of the following animal oils:
Fish oils, animal foot oils and tallows.
The animal oils which can be used are preferably animal foot oils, in particular neatsfoot oil.
The dihydric or polyhydric alcohols which can be used may comprise dihydric alcohols such as ethylene glycol, propylene glycol, butylene glycol, pentylene glycol, hexylene glycol and polyethylene glycols such as diethylene glycol, triethylene glycol, polypropylene glycols such as dipropylene glycol, trihydric alcohols such as glycerol, tetrahydric alcohols such as threitol, erythritol, pentahydric alcohols such as arabitol, adonitol, xylitol, hexahydric alcohols such as sorbitol, mannitol, dulcitol, or higher polyhydric alcohols.
Preference is given to the use of dihydric and trihydric alcohols, such as ethylene glycol, propylene glycol, butylene glycol, pentylene glycol, hexylene glycol and polyethylene glycols such as diethylene glycol, triethylene glycol, polypropylene glycols such as dipropylene glycol, and trihydric alcohols such as glycerol, in particular glycerol as dihydric or polyhydric alcohol.
Without wishing to be bound to a theory, we assume that the dihydric or polyhydric alcohol prevents saponification of the vegetarian [sic] or animal fixed oil. This makes it possible to keep the mixture in a kneadable or creamy consistency for longer, so that collagen biosynthesis can be increased and improved.
A creamy, kneadable preparation is produced according to the invention from the individual ingredients. The calcium hydroxide is usually added to the preparation in amounts of 1-90% by weight, expediently 10-70% by weight, preferably 20-60% by weight, in each case based on the total weight of the preparation.
The fixed oil of vegetarian [sic] or animal origin is added to the composition to result in a creamy, kneadable consistency usually in amounts of 9-90% by weight, expediently 10-60% by weight, preferably 20-40% by weight, in each case based on the total weight of the preparation.
The dihydric or polyhydric alcohol is added to the composition to result in a creamy, kneadable consistency usually in amounts of 1-40% by weight, expediently 10-40% by weight, preferably 20-30% by weight, in each case based on the total weight of the preparation.
A preferred embodiment of the present invention relates to an abovementioned mixture which additionally comprises MgO. The MgO can be added for this purpose in amounts of 1-90% by weight, expediently 10-70% by weight, preferably 20-60% by weight, in each case based on the total weight of the preparation. However, it is assumed at present that MgO will preferably be added in smaller amounts of 10-20% by weight. MgO acts as an antacid in the bone material to counteract the acidic environment in the bone.
The ratio of calcium hydroxide to vegetarian [sic] or animal fixed oil in the mixture according to the invention can be 5/1 to 1/5, preferably 5/1 or 1/1. However, a deviation from the preferred mixing ratio may be necessary owing to the specific circumstances of the wound trauma.
If the mixture according to the invention is to have a particularly soft and smooth consistency, it is also possible to incorporate white petrolatum into it. It is usually possible to add white petrolatum in amounts of 1-60% by weight, expediently in amounts of 10-60% by weight, preferably in amounts of 20-40% by weight, in each case based on the total weight of the preparation.
Although it is not normally necessary to monitor the bone healing or regeneration process radiologically, this may nevertheless be indicated in some cases. In this case, it is also possible to incorporate barium sulfate as X-ray contrast agent into the mixture according to the invention. However, since the collagen regeneration resulting with barium sulfate is somewhat less good, the amount of barium sulfate added to the mixture according to the invention if necessary is just sufficient (for example 10-20% by weight based on the total weight of the preparation) for the mixture just to be radiographically visible.
Application of the mixture according to the invention onto or into the bone injury can take placexe2x80x94depending on its consistencyxe2x80x94by use of syringes, spatulas or brushes.
There are numerous possible uses of the mixture according to the invention in general surgery and oral surgery, orthopedics, implantology, traumatology and the like, because the mixture according to the invention can be applied onto or into bone tissue injuries such as fracture surfaces, drillings, cavities and the like and immediately induces in vivo collagen regeneration at the particular site of application.
Since, as is well known, metallic fixing means are used in some relevant medical disciplines, it is advisable in this case to fill the drilling prepared for insertion of the fixing means with the mixture according to the invention before insertion of the fixing means, and only then to introduce the fixing means. It is possible in this way to counter the primary osteolysis unavoidable with such procedures and thus speed up the fitting or adaptation of the fixing means in or to the surrounding bone tissue and the fixing of the fixing means itself by the bone tissue.
Excess mixture moreover does not interfere in this case because on introduction of the fixing means into the drilling filled with the mixture either it is forced out again or diffuses into the spongiosa.
It ought to be self-evident that the mixture according to the invention and its ingredients must be both packaged and applied under sterile conditions.
It has also emerged in an extremely surprising manner that the mixture according to the invention counteracts, even without antibiotic and/or corticoid assistance, an inflammatory reaction caused by the bone injury, and rapidly causes it to subside. Its simple composition and pronounced efficacy for in vivo collagen regeneration with simultaneous inhibition of inflammation make the mixture according to the invention a composition which will be indispensable in future in bone traumatology.
The following examples are intended to illustrate the invention in detail.